Thienyl and pyridyl esters



Patented May 12, 1953 UNITED STATES 2,6387171;

AND PYRIDEH; ESTERS" Alfred" Burger; Gliarl'ottesville Val, assigznor 303 Smith, Kline & French Laboratories, Phil'adel phia, Pa., a; corporation of, Bennsylvarfia.

No'Drawing. Application June-15,- 1948,"- Serial No. 339220:

This invention relates to certain new chemical compounds which may be more particulgarly defined as thienyl and pyridyl cyclo'alky-l estersand which have; physiological activity-more particuaQM- Q Ji PQahe i aec in spasmcdioac ivi and to method involved in their preparation Broadly speaking, the compounds contemplated by thisdnvention will be illustrated by the following general st ucture;

in which Y is a, member of the group consisting of Z-thienyl andsz-pyridyl; R is hydrogen when Y is 2;-.pyridy1 andyR isihydrogenior Zethienyl when Y is 2 -thienyl; R." is a member of the group consisting of hydrogen, aryl and substituted aryl; R/ is -an-alkyleneugroup-ot2not-more than 3 carbon atoms-and'vXrisi-aimemberi otitheu, group consisting of tertiary nitrogen linked amino groups containing a member of -the-group consisting of two alkyl groups, two alicyclic groups andra,.-heterocyc1iez structure It is believed that physiological activities of the compounds in accordance with this invention reside in .thezifactuthatitheysareiamino alcor hol esters of thsemniqueisubstitutedscyclopropane carboxylic acids.

Generally speaking, the compounds in accordance witlrthis invention, and having the ;structure Of; the above igeneraliformuiar wilt-be prepared by procedure involving the method in accordance with this invention by reacting ethyl diazoacetate. ZI-Vinylia pyridine, which; is known to the art, i or Zevinyl thiopheneg. whichvis; known to the art, depending upon whether a pyridyl or a thienyl compound is to be produced for the formation of an ester, converting the ester t tneicorresnondi ei diziom x m e. y 40 saponification of the ester, and esterifying the acid by any well known procedure, as by convertingnt'o the -acid:' chloride, byianyiwelli known-pro cedure, as, for example by treatment alcohol having the desired substituent for X, as defined i inconnection with the above general formula, on treating the aciddillfiqtly with; the amino alqohol in the presence ci ar-catalyst.

As more specifically illustrative of compounds (Cl. 26.0.,s247 .21)

1. 9; dailies-with; this-invention; and. as; iltuse. ail i procedure fora-"their" production; torixample-i Exammesh oll ctedt Th latter fraction;is--refractionatecti.,

nd-v3.6! a ha-di ill te, BLiP4'1-20l.5-'121-5% 533111; is obtained;

2;.(2-pyridyl1rcyclopropane carboxylic acid. A

solu iomoi-wiai itheiester -u-r-5o1cc. of ethanoL 1 is;m-i xed1with a suspension; e8; g ofiisodium; hydroxide in 91cc: ofwater; mixture is: r fluxed f rix. hours @and theivelatile solvents are remoyed., Thee-solid: residuea-istdriied in? desiccator anditheny-boiledwith.-;- 51cc; of-;thionyl chlorldezifors six hoursi: EXQESS athionylxchloridev lS.-- remoyed under reduced pressuresthe-z lasta traces; wi h: the soi, benzenee Thesdark carry:

residue) is decomposed wither-water; The: solution;

isiclariiie d with: ;-cha11c 0a1.- andsthe filtrate rist-neu-etral zeu to pH? 6.3 a with. mmonium hydroxides haustivet xtrac i nawitht ether "re flfiei sfafl at: mostcQlQl'lQSs crystalline-acidwhich is rrecrystals;

gigeg from, benzene-petroleum ether to Mt R The hydeochlorides preparediinvethemsolution, consistsf ,colorlessicrystalsi M i8i 89c Est nficiaiioniiomhe carboxyliciacid :fomproL-rv duction of the end product will be effeeted'casm thionyl chloride, and treating with an amino Of ra s f ribxacidi The mixture dred over sodium sulfate and fractionated.

Example 2 Ethyl 2-(2-thienyl) -cyclopropane carboxylate will be prepared as follows:

A mixture of 9 g. of ethyl diazoacetate and 4 g. of 2-vinylthiophene (prepared according to Nazzaro and Bullock, J. Am. Chem. 1800., 68, 2121 (1946) is condensed as described for the pyridine analog, and 3 g. of the ester, B. P. 115117 (4 mm.) is obtained.

2-(2-thienyl) cyclopropane carboxylic acid will be prepared as follows:

Three grams of the ester is saponified with a solution of 1 g. of sodium hydroxide in 30 cc. of ethanol and 2 cc. of water by refluxing for seven hours. The alcohol is distilled, the residual solution diluted with 50 cc. of water and extracted with ether. Acidification of the alkaline aqueous solution gives an oily material which crystallizes on standing at 4. The dried material is converted to the acid chloride by, refluxing for four hours with 22 cc. of thionyl chloride, the excess reagent is removed, and the oily acyl halide is distilled. It boils around 107 (4-mm.).

Decomposition of the pale yellow oil with water renders an oily product which crystallizes soon.

Recrystallization from water at 45 and cooling leads to colorless crystals, M. P. 58-60.

Esterification of the carboxylic acid for production of the end product will be effected as follows:

(a) One gram of the acyl chloride is dissolved in cc. of dry ether, and 0.8 g. of tropinol dissolved in 10 cc. of benzene is added at 20. After standing overnight, absolute ether is added to complete the separation of the tropinol ester salt, and this is filtered and recrystallized.

(b) 1.6 grams of the acid is treated with a so lution of 0.9 g. of dimethylaminoethanol in 10 cc. of toluene. 1 cc. of concentrated H2804 is added, the mixture is refluxed for '7 hours and worked up by neutralization with aqueous alkali, drying of the toluene solution and fractionation.

-Having prepared the pyridylcyclopropane carboxylic acid or the thienylcyclopropanecarboxylic acid as described in Examples 1 and 2 above, the

various products in accordance with this invention and as defined in the above general structural formula may be prepared by following the esterification procedure described in Examples 1 and 2, or other well known esterification procedure using an amino alcohol having the substituent for the particular product within the above general formula.

A wide variety of amino alcohols may be used in the preparation of the new esters. Among the amino alcohols which may be used are the following:

,B-Dimethylaminoethanol S-Diethylaminoethanol B-Dibutylaminoethanol 2-piperidinoethanol 2- (4-morpholinoethanol) Tropine Phenylethylamino ethanol 3-piperidinopropanol 2-piperidinopropanol 4 3-diethylaminopropanol B-dimethylaminopropanol 3-dipropylaminopropanol 3-di-n-butylaminopropanol 3-piperidinopropan-1,2-diol As more particularly illustrative of specific compounds of various types in accordance with this invention having the structure of the above general formula, the following will be noted:

1- (fl-diethylaminoethyl) -2- (Z-thienyl) cyclopropane carboxylate having the formula l-(p dimethylaminoethyl) -2(2 thienyl) cyclopropane carboxylate having the formula CH2 CH2C2 1-(3 piperidinopropyl) -2-(2 thienyl) cyclopropane carboxylate having the formula 1-(2 piperidinopropyl) -2-(2 -'thienyl) cyclopropane carboxylate having the formula /CH2-CH2 -CHCHCOOCH2CHN CH2 CH2 CH3 CHz-CH2 1- (Z-diethylaminoethyl) -2- (Z-pyridyl) cyclopropane carboxylate having the formula 1- (2-piperidinoethyl) -2- (2-pyridyl) cyclopropane carboxylate having the formula 1-(3-di-n-propylaminopropyl) -2- (2 pyridyl) cyclopropane carboxylate having the formula 1-tropiny1-2-(2-pyridyl) cyclopropane carboxylate having the formula 1-(2-diethy1aminoethyl) -2,2 bis (2 thienyl) cyclopropane carboxylate having theformula The starting material for this compound, 1,1-bis- (Z-thienyl) ethylene, may be prepared by the method of Nahke, Ben, 30, 2038 (1893).

1-(3-dimethylaminopropyl) 2 -(2 -pyridyl) -3- phenylcyclopropane carboxylate having the formula @on on-ooocmomommoam o JOHS This compound may be prepared starting from a-stilbazole.

1- (Z-piperidinoethyl) -2- (2-pyridyl) -3- (i-chlorophenyl) cyclopropane carboxylate having the formula CH2-CH2 01 This compound may be prepared from p-chloroa-stilbazole which can be obtained by the general method of Shaw and Wag'stafi, J. Chem. Soc., 1933, '77.

1-(2-diethylaminoethyl) 2 -(2- pyridyl) -3-(4- methoxyphenyl) cyclopropane carboxylate having the formula I (32 CH-CHCO O CHzGHzN N 6 What I claim and desire to protect by Letters Patent is:

1. Compounds having the structure:

in which Y is a radical selected from the group consisting of 2-thieny1 and 2-pyridy1; R is an alkylene group of not more than 3 carbon atoms, and X is selected from the group consisting of piperidino, morpholino and lower dialkyl amino groups.

2. 1- (2-diethyl-aminoethyl) 2 (2 -pyridyl) -cyclopropane carboxylate 3. 1-[2-(4-morpholinoethyl) l- 2 -(2 pyridyl) cyclopropane carboxylate CHr-CHi CHCHCOOCH2CH2-N C 2 CHz-C 2 4. l-(p dimethylaminoethyl) -2 '(2-thienyl) cyclopropane carboxylate CH2 5. I-(Z-piperidinoethyl) 2 -(2-pyridyl) -cyc1opropane carboxylate 6. l-(2-piperidinopropyl) -2- (2-thienyl) -cyclopropane carboxylate ALFRED I BURGER.

References Cited in the file 01. this patent UNITED STATES PATENTS Number Name Date 2,425,723 Blicke Aug. 19, 1947 2,501,858 Suter Mar. 28, 1950 FOREIGN PATENTS Number Country Date 249,036 Switzerland Mar. 16, 1948 OTHER REFERENCES Beil'stein, Vierte Aufiage, vol. 9, page 619. Hartman: California and Western Medicine, 66 (No. 4), 242-248 (1947). 

1. COMPOUNDS HAVING THE STRUCTURE: 